Abstract
Abstract 820
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with hematological malignancies. However, its success is limited by life-threatening graft-versus-host disease (GVHD). Novel approaches are needed to control GVHD. Recent studies have shown the importance of histone methylation in regulating the expression of genes associated with effector T cell differentiation and proliferation. Using several mouse models of allo-HSCT, we report that in vivo administration of the histone methylation inhibitor 3-Deazaneplanocin A (DZNep) arrested ongoing GVHD while preserving graft-versus-leukemia activity (GVL). To assess the therapeutic effect of pharmacologic modulation of histone methylation on GVHD, we administered DZNep to BALB/c mice receiving major histocompatibility-mismatched C57BL/6 mouse T cells 7 days after transplantation, in which GVHD had been fully established. Notably, injection of 12 doses of DZNep controlled the disease in these recipients, with approximately 80% of them surviving long-term without significant clinical signs of GVHD. We found that in vivo administration of DZNep caused selective apoptosis in alloantigen-activated T cells, but did not impair the generation of effector T cells that produced inflammatory cytokines (e.g., TNF-α, IFN-γ and IL-17) and cytotoxic molecules (e.g., granzyme B and Fas ligand). As a result, alloreactive T cells retained potent GVL activity, leading to improved overall survival of the recipients challenged by leukemic cells. These data suggest that DZNep-mediated inhibition of GVHD may be accounted for by reduced number of alloreactive effector T cells. In vitro culture assays showed that DZNep treatment induced apoptosis in T cells activated by anti-CD3/CD28 antibodies but not in naive T cells stimulated by IL-2 or IL-7. This effect was associated with DZNep's ability to selectively reduce trimethylation of histone H3 lysine 27 (H3K27), deplete the histone methyltranferase Ezh2 that specifically catalyzes trimethylation of H3K27, and activate Ezh2-repressed pro-apoptotic gene Bim. Inactivation of Bim partially protected alloreactive T cells from DZNep-mediated apoptosis. Importantly, unlike DNA methylation inhibitors, inhibition of histone methylation by DZNep had no toxicities to hematopoietic cells or impairment on the reconstitution of hematopoiesis and thymopoiesis. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat established GVHD and other T cell-mediated inflammatory disorders in a broad context.
Disclosures:
No relevant conflicts of interest to declare.
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